PROJECT SUMMARY Sickle cell anemia (SCA) is a rare disease in the United States, affecting primarily African-Americans, who are often poor, and without a strong health advocacy presence. Neurological complications of the disease are critically important. Our team has shown that silent cerebral infarcts are progressive; approximately 50% of adults with SCA will have silent cerebral infarcts and 10% will have an overt stroke by age 30. My patient- oriented research (POR) program focuses on elucidating the mechanisms of brain injury and assessing infarct risk in children and adults with SCA. Herein, I propose to become an outstanding patient-oriented research mentor to a diverse group of undergraduate/graduate students, postdoctoral fellows, and junior faculty trainees from multiple disciplines and continue to extend my research to better understand the pathogenesis and burden of cerebral infarcts in adult SCA. Based on strong preliminary data from our research team in adults and children with SCA, my aims include: 1) to determine in a multicenter collaborative group, the incidence of new silent infarcts and overt strokes in adults (?18 years of age) with SCA, with and without infarcts at baseline; 2) to apply advanced brain imaging methods for stroke risk stratification in adults with SCA across multiple sites. Newer non-invasive MRI methods such as diffusion tensor imaging (DTI) techniques assessing white matter microstructure and methods that assess cerebral hemodynamics will identify areas of subtle brain injury and hemodynamic signatures that may predict increased stroke risk. These imaging methods could then be applied to future clinical trials focused on applying aggressive stroke prevention strategies for adults with SCA at highest risk of progressive infarcts. I have involved mentees in each of my aims, developed a formal plan to train junior investigators in patient-oriented research, and created a formal senior mentoring advisory committee. I plan to learn new neuroimaging skills for myself and use resources available from my research program and the Vanderbilt Institute for Clinical and Translational Research to support my mentees. I have a strong record of funded patient-oriented research and training mentees but require the protected time and further education to become the inspiring mentor I envision. Mentoring the next generation of patient-oriented researchers is important for sustaining research progress and creating a legacy of investigators in the neurological complications of SCA, particularly as the patient lifespan increase. The combination of a multidisciplinary research team for mentees to learn from, an outstanding research and institutional environment, and a strong mentoring plan are key to the success of this proposal.